Nerve cells are particular tissues, which has no mitotic potential in an adult. Therefore, once they are injured, the damage will last over a long period of time. It is said that there is no regeneration potential especially in the central nervous system (CNS) such as brain and spinal cord. Lack of the regeneration potential in the central nerves can be regarded as one of the reasons that there have been no established therapies for traumatic injuries such as spinal cord injury, nor for neurodegenerative diseases such as Alzheimer's disease and Parkinson disease. On the other hand, peripheral nerves possess regeneration potential. Their axons can regenerate and their functions can be recovered even after having been severed. In this case, however, the recovery requires a long span of time ranging from several months to even more than a year, and thus patients have to undergo considerable sufferings. Moreover, the recovery period is so long that some nerve cells may die during this period, which often leads to the failure of recovery of the functions. And yet, even the peripheral nerves having regeneration potential are entirely unable to outgrow in the CNS such as in brain and spinal cord. This brings the basis for the hypothesis that there exist some substances in the central nervous system that inhibit nerve outgrowth. If the inhibitory substances for nerve regeneration in the central nervous system are suppressed by using antibodies or the like, nerve regeneration in the CNS as well as the recovery of their functions will be observed, even though partially. As one of such inhibitory substances for the central nerve regeneration, Nogo has been recently discovered (Nature 403, 434, 2000, Nature 403, 439, 2000). However, only a small portion of axons are regenerated by inhibiting Nogo and it is thus presumed that there exist some other regeneration-inhibitory substances. The followings are exemplified as candidate substances that inhibit the nerve regeneration: MAG (myelin-associated glycoprotein); tenascin; gangliosides; ephrin; netrin; slit; semaphorins and the like. The only reason for these substances to be exemplified as the candidate substances is that they inhibit neurite outgrowth in vitro. Whether they actually act to inhibit nerve regeneration in vivo has not yet been elucidated so far.
Referring to semaphorin, its gene was first isolated as a factor involved in nervous system formation in developing locusts. Since then, it has been reported that semaphorins constitute a large gene family distributing in nematodes, fish, mammals or even certain kinds of virus, and currently semaphorin genes are classified into eight gene subfamilies or classes based on their structures (Cell 97, 551, 1999). Semaphorin is an endogenous protein identified as a factor which collapses nerve growth cone and suppresses axon outgrowth, and so far, about 20 molecular species have been reported (Cell 97, 551, 1999). However, most functions of many semaphorin families have not yet been discovered in detail. The most studied gene group is that of a subfamily called the class III type, all of whose translation products are secretory proteins. Although proteins encoded by these genes are known to possess intensive neurite outgrowth suppressing activity and growth cone collapse activity in vitro, it was reported that they induce neurite outgrowth under certain conditions. Among them, semaphorin 3A (Sema3A) is the most studied and is known to induce growth cone collapse of the cultured nerve cells at as low as 10 pM concentration in a short period of time (Cell 75, 217, 1993, Cell 75, 1389, 1993). In order to analyze in vivo functions of semaphorins, knockout mice for neuropilin-1, which is one of the components of Sema3A receptor, have been studied (Neuron 19, 995, 1997). The said knockout mice show embryonic lethality as well as motor abnormality in some nervous systems such as trigeminal nerve and angiogenesis abnormality. Although similar motor abnormality in nervous systems is observed in Sema3A knockout mice, some individual mice are reported to grow up to adults without serious problem. Therefore, the in vivo functions of Sema3A remain largely unknown.
Moreover, with regard to semaphorins the followings are also known: antisense nucleototides and antagonists such as antibodies or the like for semaphorin W, semaphorin Y and semaphorin Z are made for central nerve regeneration promoters (WO98/15628, WO98/11216, WO98/20928); and a method of inducing neurite outgrowth by contacting a nerve cell with an antibody that specifically binds to human collapsin is known (U.S. Pat. No. 5,416,197). However, in vivo actions of these antibodies or the like still remain unknown. Besides, any low-molecular weight compounds other than peptide or nucleotide such as an antibody or an antisense nucleotide or the like, which specifically inhibits semaphorin have been completely unknown.
The subject of the present invention is to provide semaphorin inhibitors, peripheral or central nerve regeneration promoters that contain the said semaphorin inhibitors as an active ingredient, preventives and remedies for neuropathic diseases and neurodegenerative diseases that contain the nerve regeneration promoters.